Atherogenesis may be associated with increased transport of low density lipoproteins (LDL) into the arterial wall. Normal transport rates may be enhanced by mechanical, chemical, or immunological injury to the endothelium. The objectives of the proposed research are to determine (a) how rapidly LDL enters the arterial wall, (b) whether the lipid and protein moieties enter and accumulate at the same rate, (c) the extent to which perturbations from the normal state, particularly endothelial injury, influence LDL transport, and (d) the transport mechanisms which may be important and the magnitude of the transport parameters. We plan to measure aortic transmural concentration profiles and total uptake of radioiodinated LDL and albumin at specific times following injection into rabbits, using techniques we have previously developed. These experiments will be carried out in normal controls and in studies designed to determine the effects of various interventions upon LDL transport and accumulation. These interventions include (1) mechanical de-endothelialization using a balloon catheter with normolipemic, hypercholesterolemic and/or thrombocytopenic rabbits studied at different times followin de-endothelialization and after re-endothelialization; and (2) nonmechanical injury, including hypercholesterolemia, hypertension, and chemical injury. The parameters of LDL and albumin transport will be correlated with the histology and morphology of the injured and healing arterial wall. We intend to develop doubly-labeled LDL containing stable, distinguishable, and nonexchangeable radioactive labels on both lipid and protein moieties so that the transport stoichiometry can be assessed. We plan to develop techniques for ultrastructural localization of LDL by electron microscopy using an immunoperoxidase method. We also intend to continue development of theoretical models of macromolecular transport across the arterial wall for comparison with experimental data. The experiments outlined above will be selectively extended to primates.